Iglesias Guerra, FernandoDíaz Herrero, María del MarCampo, José Antonio delCarbonero Aguilar, María del PilarVega Pérez, José ManuelPeriñán Domínguez, IgnacioMiñano Sánchez, JavierBautista Palomas, Juan DionisioRomero Gómez, Manuel2016-03-102016-03-102014Iglesias Guerra, F., Díaz Herrero, M.d.M., Del Campo, J.A., Carbonero Aguilar, M.d.P., Vega Pérez, J.M., Periñán Domínguez, I.,...,Romero Gómez, M. (2014). THDP17 decreases ammonia production through glutaminase inhibition. A new drug for hepatic encephalopathy therapy. (Tesis Doctoral Inédita). Universidad de Sevilla, Sevilla.1932-6203http://hdl.handle.net/11441/38362Ammonia production is implicated in the pathogenesis of hepatic encephalopathy (HE), being intestinal glutaminase activity the main source for ammonia. Management of ammonia formation can be effective in HE treatment by lowering intestinal ammonia production. The use of glutaminase inhibitors represents one way to achieve this goal. In this work, we have performed a search for specific inhibitors that could decrease glutaminase activity by screening two different groups of compounds: i) a group integrated by a diverse, highly pure small molecule compounds derived from thiourea ranging from 200 to 800 Daltons; and ii) a group integrated by commonly use compounds in the treatment of HE. Results shown that THDP-17 (10 µM), a thiourea derivate product, could inhibit the intestinal glutaminase activity (57.4±6.7%). Inhibitory effect was tissue dependent, ranging from 40±5.5% to 80±7.8% in an uncompetitive manner, showing Vmax and Km values of 384.62 µmol min−1, 13.62 mM with THDP-17 10 µM, respectively. This compound also decreased the glutaminase activity in Caco-2 cell cultures, showing a reduction of ammonia and glutamate production, compared to control cultures. Therefore, the THDP-17 compound could be a good candidate for HE management, by lowering ammonia productionapplication/pdfengAttribution-NonCommercial-NoDerivatives 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/articleinfo:eu-repo/semantics/openAccesshttps://doi.org/10.1371/journal.pone.0109787